Inflammatory Bowel Disease (IBD) affects over 1 million people in the United States and can cause numerous complications such as malnutrition, infection, severe pain, and an elevated risk of developing colorectal cancer. Despite concerted research efforts, the fundamental pathophysiology of IBD remains unclear. Homeostasis in the intestine is maintained through continual proliferation, differentiation, and repair in response to injury. Dysregulated repair programs are thought to be critical to IBD pathology. Epithelial-to- mesenchymal transition (EMT) is a process by which epithelial cells acquire more mesenchymal phenotypes and is pivotal to injury-repair. Regulation of EMT in response to intestinal injury remains unclear and complex, and uncovering how EMT is altered in IBD could have significant therapeutic implications. Blood vessel epicardial substance (BVES) is a tight junction-associated protein discovered in a cDNA screen of a developing heart. We recently reported that that loss of BVES promotes EMT in corneal epithelial and malignant cell lines. This is partially the result of BVES-mediated regulation of WNT and RhoA activity (Williams et al. 2011 JCI). However, manipulating these systems does not completely rescue BVES-dependent phenotypes, indicating other signal transduction pathways are regulated by BVES. Therefore, we conducted a yeast-two-hybrid screen with the BVES intracellular domain and identified RSK1, a serine/threonine kinase that regulates cellular proliferation, survival, and motility, all cellular processes that are critical to epithelial injury recovery and influenced by BVES. We have generated preliminary data to indicate that mice lacking BVES have increases in intestinal permeability and proliferation, as well as altered secretory lineage allocation. Bves-/- mice also demonstrate increased mucosal injury in both chemical and infectious colitis models, with dysregulated cytokine production at baseline and in response to injury. Given these observations, we hypothesize that BVES, a tight junction-associated protein recently discovered to regulate EMT, is a key regulator of mucosal integrity and signals through RSK1. We propose to test these hypotheses via a twofold approach by: 1) Examining the role of BVES in maintaining mucosal integrity after inflammatory intestinal injury models in mice, and 2) Determining the functional significance of the BVES:RSK1 interaction by mapping their binding domains and determining how disrupting the interaction affects BVES- dependent phenotypes. Collectively, these experiments will use a combination of genetically engineered mice, cell lines, and a newly-developed enteroid platform to investigate the role of BVES in mucosal integrity and its potential merit as a therapeutic target in IBD.